Abstract Dietary triglycerides (TGs) are the main source of the total energy from ingested lipid. Lipid absorption occurs in jejunum and begins with the uptake of free fatty acids by enterocytes for their re-esterification into TGs at the ER membrane. TGs are either transiently stored as lipid droplets (LDs) or are released into circulation as chylomicrons. Increased dietary fat and elevated blood TG levels (hypertriglyceridemia) are major determinants of cardiometabolic disease. Macroautophagy (MA) is a cellular recycling program that maintains quality control by degrading cellular constituents in lysosomes. MA maintains lipohomeostasis by degrading lipid droplets (LDs) in lysosomes via lipophagy. Whether lipophagy degrades LDs in enterocytes and protects against hypertriglyceridemia remain unknown. Mechanistic target of rapamycin (mTOR), a serine/threonine kinase, suppresses MA and promotes growth and proliferation. Whether mTOR regulates lipophagy is unclear. Our preliminary data show that availability of fatty acids activates both mTOR signaling and MA. Since hyperactivation of mTORC1 or suppression of MA in gut each increased the absorption of dietary TGs and led to hypertriglyceridemia, we hypothesize that a balance between mTOR and MA controls fat absorption?while activation of mTOR maximizes lipid absorption by suppressing lipophagy, lipophagy limits the entry of TGs into circulation by degrading cytosolic LDs in enterocytes. Since aging associates with hyperactivation of mTOR and MA failure, we propose that age-associated imbalance between mTORC1 and lipophagy in gut promotes hypertriglyceridemia and metabolic disease. Neurons in the mediobasal hypothalamus (MBH) play an important role in peripheral lipid metabolism. MA is required by MBH proopiomelanocortin (POMC) neurons to activate peripheral lipophagy and maintain lipohomeostasis. We hypothesize that MA in POMC neurons maintains lipohomeostasis by stimulating lipophagy in enterocytes. Our preliminary studies in a mouse model of Alzheimer?s disease (AD) (harboring the human mutant Tau) revealed that onset of hypertriglyceridemia in these mice associates with the spread of Tau to MBH. Based on these data, we hypothesize that MA in POMC neurons is required to activate lipophagy in gut, which protects against hypertriglyceridemia/metabolic syndrome by degrading TGs in enterocytes. We hypothesize further that loss of MA in POMC neurons with age or during AD pathogenesis impairs lipophagy leading to metabolic dysfunction. We propose the following aims: Aim 1: Determine the role of gut lipophagy in hypertriglyceridemia/metabolic syndrome in aged mice. We will determine whether mTORC1 signaling and lipophagy are altered in aged mice, and that mTORC1 suppresses lipophagy by localizing to LDs. We will use cholesterol-supplemented HFD in young/aged mice to determine whether dampened lipophagy leads to metabolic syndrome. Aim 2: Dissect the interplay between hypothalamic MA and gut lipophagy in lipohomeostasis. We will determine whether lipid availability stimulates MA in POMC neurons, and that this activation of MA in POMC neurons is dampened with age. We will determine whether stimulation of MA in POMC neurons induces lipophagy in jejunum by decreasing the abundance of mTOR at the LD surface, and whether this protects against hypertriglyceridemia. Aim 3: Explore whether failure of hypothalamic MA-gut lipophagy axis disrupts lipohomeostasis in AD. We will determine whether MA in POMC neurons is disrupted in mice harboring the human mutant Tau, and whether this decreases lipophagy and promotes metabolic defects. We will explore whether stimulating lipophagy normalizes metabolic function in AD mice. Significance: Metabolic syndrome of aging occurs in part from increased intake of dietary TGs. Understanding the contribution of gut lipophagy to absorption of dietary TGs will help develop approaches to lower blood TG levels, which will protect aged individuals against type 2 diabetes and Alzheimer?s disease.